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Dear All,
Ketoconazole is well described in literature as a potent inhibitor of
CYP3A4 both in vitro and in vivo in man. In addition, ketoconazole is
also
an inhibitor of Pgp in vitro. The IC50 is about 1µM on the transport of
Digoxin which is similar to the plasma concentration after dosing 200mg
b.i.d.
Does anyone know some literature showing that ketoconazole is also an
inhibitor in vivo in man of Pgp ? I have only found one publication in
rat
(Benet at all, Pharmacology, 1998;56:308-313).
Many thanks in advance
Dr Hugues Dolgos
Head of Metabolism, Bioanalytics and labelling
Institute of Drug Metabolism and Pharmacokinetics
Merck KGaA
Am Feld 32
D-85567 Grafing
Germany
Phone: +49 (0)8092 - 700868
Fax: +49 (0)8092-700899
Email : hugues.dolgos.-at-.merck.de
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Dear Dr Dolgos,
Here is a list of some articles showing the inhibitory effects of
ketoconazole on some drugs that are both P450 and P-gp substrates. I
hope that it will help!
Houda Hachad
Khaliq Y, Gallicano K, Venance S, Kravcik S, Cameron DW.
Effect of ketoconazole on ritonavir and saquinavir concentrations in
plasma and
cerebrospinal fluid from patients infected with human immunodeficiency
virus.
Clin Pharmacol Ther. 2000 Dec;68(6):637-46.
Akhlaghi F, Keogh AM, McLachlan AJ, Kaan A.
Pharmacokinetics of cyclosporine in heart transplant recipients
receiving
metabolic inhibitors.
J Heart Lung Transplant. 2001 Apr;20(4):431-8.
Tuteja S, Alloway RR, Johnson JA, Gaber AO.
The effect of gut metabolism on tacrolimus bioavailability in renal
transplant
recipients.
Transplantation. 2001 May 15;71(9):1303-7.
Floren LC, Bekersky I, Benet LZ, Mekki Q, Dressler D, Lee JW, Roberts
JP,
Hebert MF.
Tacrolimus oral bioavailability doubles with coadministration of
ketoconazole.
Clin Pharmacol Ther. 1997 Jul;62(1):41-9.
Kehrer DF, Mathijssen RH, Verweij J, de Bruijn P, Sparreboom A.
Modulation of irinotecan metabolism by ketoconazole.
J Clin Oncol. 2002 Jul 15;20(14):3122-9.
Houda Hachad, Pharm D
Research Associate
Metabolism & Transport Drug Interaction Database
University of Washington, Seattle
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The following message was posted to: PharmPK
The article by Khaliq et al. (Clin Pharmcol Ther 2000;68:637-46) gives
indirect evidence via increases in CSF/plasma unbound ratio that
ketoconazole inhibits efflux transport of ritonavir from CSF to plasma.
Keith
Associate Director, Biopharmaceutics
Watson Laboratories, Inc.
311 Bonnie Circle, P.O. Box 1900
Corona, CA 92878-1900
tel: 909-493-4012
fax: 909-493-5819
toll free: 1-800-249-5499 ext 4012
e-mail: kgallicano.-a-.watsonpharm.com
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